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Rapamycin use and rapid withdrawal of calcineurin inihibitors in pediatric renal transplantation
Rapamycin Use and Rapid Withdrawal of Calcineurin Inihibitors in Pediatric Renal Transplantation R. Vilalta, A. Vila, J. Nieto, and L. Callı´s
T
HE AIM OF THE PRESENT STUDY was to assess the safety and efficacy of sirolimus (rapamycin) in pediatric renal transplantation over a period of 12 months as only few reports dealing with this subject are available.1,2 Sirolimus (Rapamycin, Rapamune, Wyeth-Ayerst Pharmaceuticals) shows improved rejection prophylaxis in adults renal transplant patients when used either alone or combined with cyclosporine or tacrolimus added to a classic mycophenolate low-dose corticoid regimen.3,4 Since tacrolimus and sirolimus have the same intracellular target, namely the FKBP12 protein, and sirolimus appears to be less nephrotoxic than cyclosporine or tacrolimus, it seems interesting to use sirolimus alone (plus mycophenolate and corticoids) after rapid withdrawal of cyclosporine or tacrolimus. The mechanism of action of sirolimus differs from that of cyclosporine and tacrolimus.5 Both of the latter two drugs inhibit the first phase of T-cell activation by blocking calcineurin and IL-2 production, and inhibits subsequent T-cell activation. In contrast, sirolimus interferes with the second phase of T-cell activation by interrupting the signal from the IL-2 other cytokine and growth factor receptors by blocking the signal transduction pathway required for progression from the G1 into the S phase, thus suppressing interleukin-driven T-cell proliferation. PATIENTS AND METHODS Inclusion Criteria Six patients of both sexes (three boys, three girls) who received their first kidney transplant were included in the study. All received two doses of basiliximab. They also received immunosuppression with rapamycin, mycophenolate, 6-methyl-prednisolone, and cyclosporine. Ages ranged from 2 to 18 years (mean, 11 years) and body weight from 10 to 50 kg (mean, 25 kg). Informed consent was signed by the parents in all cases. All patients were recipients of a cadaver donor kidney.
Treatment Protocol Rapamycin was administered orally immediately pretransplant (1.15 mg/m2 per 24 hours). Cyclosporine was also administered by mouth separated by 3 hours from rapamycin (5 mg/kg per 24 h). Methyl-prednisolone (5 mg/kg per 24 hours) and mycophenolate were added to the immunosuppressive regimen. Prophylaxis against CMV was administered to all patients with ganciclovir (5 mg/kg per day) intravenously for 8 weeks. Cyclosporine was © 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 703–704 (2003)
withdrawn in all cases during the first week posttransplant. The dose was stopped in 7 days or less, when therapeutic levels of rapamycin were achieved. Rapamycin levels were maintained as rough concentrations between 4 to 12 ng/mL as determined by HPLC with UV detection. Cardiovascular risk factors were evaluated. Mycophenolate levels were maintained between 2 and 5 g/mL (mean: 3.5 g).
RESULTS Evolution
No rejection episodes were observed among the patients during the time of evolution. Immediate diuresis was observed in four cases and delayed for 3 and 5 days in the other cases. Rapamycin therapeutic levels were attained between 3 and 5 days of treatment (mean, 3.4 days). No rejection episodes were detected; the delay in diuresis in two cases was attributed to acute tubular necrosis. All patients presented normal creatinine levels within 14 days (range, 2 to 14 days; mean, 5 days). Lipid results were (millimol) total cholesterol 6.3 ⫾ 0.1; triglycerides 2.5 ⫾ 0.1, LDL-C 3.5 ⫾ 0.1, HDL-C 1.6 ⫾ 0.07, LDL/HDL 2.4 ⫹ 0.1. No adverse effects or opportunistic infections were observed. The patients exhibited significantly greater apparent rapamycin oral clearances after cyclosporine withdrawal, requiring the Rapamycin dose to be increased by a mean range of 40% (range, 20% to 50%). The half-life of sirolimus was shorter and the clearance greater in patients under 11 years. Twelve months after transplant, all patients show normal creatinine levels and lead normal lives. DISCUSSION
Calcineurin inhibitors, such as cyclosporine and tacrolimus, have been available for almost 20 years. Although these drugs are highly effective and represent the mainstay of transplant immunosuppression, they are associated with acute and chronic nephrotoxicity. Two recently available immunosuppressive agents, mycophenolate mofetil and sirolimus (rapamycin) have no nephrotoxicity. The use of From the Servicio Nefrologı´a-Hemodia´lisis, Hospital MaternoInfantil Vall d’Hebron, Barcelona, Spain. Address reprint requests to Dr Ramon Vilalta, Pediatric Nephrology, Hospital Mat-infantil, Vall D’Hebron, Pg. Vall D’Hebron 119-129, 08035 Barcelona, Spain. 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00055-1 703
704
these drugs has led to the development of new approaches in immunosuppressive therapy. Although hyperlipidemia is a common side effect of rapamycin and manageable lipid elevations have been observed, the absence of nephrotoxicity could lead to an improved long-term outcome when combined with mycophenolate and low-dose corticoids. The apparent clearance of rapamycin was increased after cyclosporine withdrawal which was attributed to a competitive inhibition between the two drugs.6
VILALTA, VILA, NIETO ET AL
REFERENCES 1. Sindhi R: First International Symposium on Sirolimus, 2001 2. Ettenger RB, Grimm EM: Am J Kidney Dis 38:s22, 2001 3. Morelo E, Mamzer-Brunecl MF, et al: Nephr Dial Transpl 16:18, 2001 4. McAlister VC, Gao Z, et al: Lancet 355:376, 2000 5. Abraham RT, Wiederrecht GJ: Annu Rev Immunol 14:483, 1996 6. Potter H, Stepkowski SM, Napoli KL, et al. J Am Soc Neph, 2001
T
HE AIM OF THE PRESENT STUDY was to assess the safety and efficacy of sirolimus (rapamycin) in pediatric renal transplantation over a period of 12 months as only few reports dealing with this subject are available.1,2 Sirolimus (Rapamycin, Rapamune, Wyeth-Ayerst Pharmaceuticals) shows improved rejection prophylaxis in adults renal transplant patients when used either alone or combined with cyclosporine or tacrolimus added to a classic mycophenolate low-dose corticoid regimen.3,4 Since tacrolimus and sirolimus have the same intracellular target, namely the FKBP12 protein, and sirolimus appears to be less nephrotoxic than cyclosporine or tacrolimus, it seems interesting to use sirolimus alone (plus mycophenolate and corticoids) after rapid withdrawal of cyclosporine or tacrolimus. The mechanism of action of sirolimus differs from that of cyclosporine and tacrolimus.5 Both of the latter two drugs inhibit the first phase of T-cell activation by blocking calcineurin and IL-2 production, and inhibits subsequent T-cell activation. In contrast, sirolimus interferes with the second phase of T-cell activation by interrupting the signal from the IL-2 other cytokine and growth factor receptors by blocking the signal transduction pathway required for progression from the G1 into the S phase, thus suppressing interleukin-driven T-cell proliferation. PATIENTS AND METHODS Inclusion Criteria Six patients of both sexes (three boys, three girls) who received their first kidney transplant were included in the study. All received two doses of basiliximab. They also received immunosuppression with rapamycin, mycophenolate, 6-methyl-prednisolone, and cyclosporine. Ages ranged from 2 to 18 years (mean, 11 years) and body weight from 10 to 50 kg (mean, 25 kg). Informed consent was signed by the parents in all cases. All patients were recipients of a cadaver donor kidney.
Treatment Protocol Rapamycin was administered orally immediately pretransplant (1.15 mg/m2 per 24 hours). Cyclosporine was also administered by mouth separated by 3 hours from rapamycin (5 mg/kg per 24 h). Methyl-prednisolone (5 mg/kg per 24 hours) and mycophenolate were added to the immunosuppressive regimen. Prophylaxis against CMV was administered to all patients with ganciclovir (5 mg/kg per day) intravenously for 8 weeks. Cyclosporine was © 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 703–704 (2003)
withdrawn in all cases during the first week posttransplant. The dose was stopped in 7 days or less, when therapeutic levels of rapamycin were achieved. Rapamycin levels were maintained as rough concentrations between 4 to 12 ng/mL as determined by HPLC with UV detection. Cardiovascular risk factors were evaluated. Mycophenolate levels were maintained between 2 and 5 g/mL (mean: 3.5 g).
RESULTS Evolution
No rejection episodes were observed among the patients during the time of evolution. Immediate diuresis was observed in four cases and delayed for 3 and 5 days in the other cases. Rapamycin therapeutic levels were attained between 3 and 5 days of treatment (mean, 3.4 days). No rejection episodes were detected; the delay in diuresis in two cases was attributed to acute tubular necrosis. All patients presented normal creatinine levels within 14 days (range, 2 to 14 days; mean, 5 days). Lipid results were (millimol) total cholesterol 6.3 ⫾ 0.1; triglycerides 2.5 ⫾ 0.1, LDL-C 3.5 ⫾ 0.1, HDL-C 1.6 ⫾ 0.07, LDL/HDL 2.4 ⫹ 0.1. No adverse effects or opportunistic infections were observed. The patients exhibited significantly greater apparent rapamycin oral clearances after cyclosporine withdrawal, requiring the Rapamycin dose to be increased by a mean range of 40% (range, 20% to 50%). The half-life of sirolimus was shorter and the clearance greater in patients under 11 years. Twelve months after transplant, all patients show normal creatinine levels and lead normal lives. DISCUSSION
Calcineurin inhibitors, such as cyclosporine and tacrolimus, have been available for almost 20 years. Although these drugs are highly effective and represent the mainstay of transplant immunosuppression, they are associated with acute and chronic nephrotoxicity. Two recently available immunosuppressive agents, mycophenolate mofetil and sirolimus (rapamycin) have no nephrotoxicity. The use of From the Servicio Nefrologı´a-Hemodia´lisis, Hospital MaternoInfantil Vall d’Hebron, Barcelona, Spain. Address reprint requests to Dr Ramon Vilalta, Pediatric Nephrology, Hospital Mat-infantil, Vall D’Hebron, Pg. Vall D’Hebron 119-129, 08035 Barcelona, Spain. 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00055-1 703
704
these drugs has led to the development of new approaches in immunosuppressive therapy. Although hyperlipidemia is a common side effect of rapamycin and manageable lipid elevations have been observed, the absence of nephrotoxicity could lead to an improved long-term outcome when combined with mycophenolate and low-dose corticoids. The apparent clearance of rapamycin was increased after cyclosporine withdrawal which was attributed to a competitive inhibition between the two drugs.6
VILALTA, VILA, NIETO ET AL
REFERENCES 1. Sindhi R: First International Symposium on Sirolimus, 2001 2. Ettenger RB, Grimm EM: Am J Kidney Dis 38:s22, 2001 3. Morelo E, Mamzer-Brunecl MF, et al: Nephr Dial Transpl 16:18, 2001 4. McAlister VC, Gao Z, et al: Lancet 355:376, 2000 5. Abraham RT, Wiederrecht GJ: Annu Rev Immunol 14:483, 1996 6. Potter H, Stepkowski SM, Napoli KL, et al. J Am Soc Neph, 2001